Secreted frizzled-related protein 5 (SFRP5) belongs to a family of secreted proteins that are antagonists for the WNT signaling pathway. It is also called SARP3. SFRPs are modular proteins that fold into two independent domains: 1) The N-terminus CRD (cystenine-rich domain) and 2) the NTR module. Chong et al., 2002, J Biol Chem., 277:5134-5144; Bovolenta et al., 2008, J Cell Sci., 121: 737-746. Biochemical studies performed in the 1990s established that SFRPs physically interact with WNT proteins to inhibit their binding to frizzled receptors and it is hypothesized this occurs via the CRD domain. Bovolenta et al., 2008.
Human SFRP5 gene is located on chromosome 10; and mouse SFRP5 gene is located on chromosome 19. Human SFRP5 is highly expressed in the retinal pigment epithelium (PRE) and pancreas, poorly expressed in heart, liver and muscle. Melkonyan et al., 1997, Proc Natl Acad Sci U.S.A., 94:13636-13641; Hu et al., 1998, Biochem Biophys Res Commun 247:287-294; Chang et al., 1999, Hum Mol Genet 8:575-583.
Several GWAS studies link WNT-signaling to diabetes and metabolic dysfunction, suggesting that targeting proteins that modulate WNT-mediated signaling may have beneficial effects on diabetes. Grant et al., 2006, Nature genetics 38:320-323; Schafer et al., 2007, Diabetologia 50:2443-2450; Saxena et al., 2006, Diabetes 55, 2890-2895; Prokunina-Olsson et al., 2009, PloS one 4:e7231; Shu et al., 2009, Human molecular genetics 18:2388-2399; Shu et al., 2008, Diabetes 57:645-653; Groves et al., 2006, Diabetes 55:2640-2644; Guo et al., 2007. Diabetes 56:3082-3088; Grant et al., 2010, Endocrine reviews 31:183-193; Lyssenko et al., 2008, The New England journal of medicine 359:2220-2232; Lyssenko et al., 2007, The Journal of clinical investigation 117:2155-2163; Guo et al., 2006, Journal of medical genetics 43:798-803; Fujino et al., 2003, Proceedings of the National Academy of Sciences of the United States of America 100:229-234; Magoori et al., 2003, The Journal of biological chemistry 278:11331-11336; Singh et al., 2013, Cell metabolism 17:197-209; Liu et al., 2012, The Journal of biological chemistry 287:7213-7223.
In 2010, Ken Walsh's group published data suggesting that ablation of SFRP5 in mice led to type 2 diabetic phenotypes that could be rescued by over-expression of adenovirus of SFRP5. Ouchi et al., 2010, Science 329:454-457. However, it has also been reported that mice that lack functional SFRP5 were resistant to diet-induced obesity. Mori et al., 2012, The Journal of clinical investigation 122:2405-2416.